Effect of Nebulized Furosemide in Terminally Ill Cancer Patients with Dyspnea

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1 962 Journal of Pain and Symptom Management Vol. 26 No. 4 October 2003 Clinical Note Effect of Nebulized Furosemide in Terminally Ill Cancer Patients with Dyspnea Hiroyuki Kohara, MD, PhD, Hiroshi Ueoka, MD, PhD, Keisuke Aoe, MD, PhD, Tadashi Maeda, MD, PhD, Hiroyasu Takeyama, MD, PhD, Ryusei Saito, MD, PhD, Yasuo Shima, MD, and Yosuke Uchitomi, MD, PhD Department of Internal Medicine (H.K., K.A., T.M., H.T.), and Palliative Care Unit (H.K., K.A.), National Sanyo Hospital, Yamaguchi; Second Department of Internal Medicine (H.U.), Okayama University Medical School, Okayama; Department of Internal Medicine (R.S.), National Nishigunma Hospital, Gunma; Palliative Care Unit (Y.S.), National Cancer Center Hospital East, Chiba; and Psycho-Oncology Division (Y.U.), National Cancer Center Research Institute East, Chiba, Japan Abstract We evaluated the effect of ultrasonically nebulized furosemide (20 mg) on dyspnea uncontrollable by standard therapy in patients with terminal cancer. Dyspnea was evaluated using the Cancer Dyspnea Scale (CDS) before and 60 min after inhalation. Changes in arterial blood gases, hemoglobin oxygen saturation (SpO 2 ), heart rate (HR), and respiratory rate (RR) also were evaluated. In 12 of 15 patients (80%), total dyspnea scores by CDS improved significantly after inhalation of furosemide (P 0.007), especially concerning a reduced sense of effort (P 0.013) and reduced anxiety (P 0.04). No significant changes were observed in the partial pressure of oxygen in arterial blood (PaO 2 ), the partial pressure of carbon dioxide in arterial blood (PaCO 2 ), SpO 2, HR, or RR. Inhalation of nebulized furosemide appears to be effective against dyspnea in terminally ill cancer patients. J Pain Symptom Manage 2003;26: U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Dyspnea, nebulized furosemide, cancer, Cancer Dyspnea Scale Introduction Dyspnea, the sensation of uncomfortable breathing, 1 is a frequent and devastating symptom in patients with advanced cancer. 2 According to Higginson and McCarthy, dyspnea Address reprint requests to: Hiroyuki Kohara, MD, PhD, Department of Internal Medicine, National Sanyo Hospital, 685 Higashikiwa, Ube, Yamaguchi , Japan. Accepted for publication: March 5, U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved. was the main symptom in 21% of terminally ill cancer patients receiving care at a community palliative care service, 3 and Ruben et al. reported that 70% of 1,754 patients with cancer experienced dyspnea during the last 6 weeks of life. 4 Although various treatments for dyspnea have been reported, this symptom remains one of the most refractory problems in terminally ill cancer patients. 5 Dyspnea usually is accompanied by tachypnea, low arterial oxygen saturation, or impairment in respiratory function test, but a definite /03/$ see front matter doi: /s (03)

2 Vol. 26 No. 4 October 2003 Nebulized Furosemide for Dyspnea 963 correlation has not been confirmed. Because the intensity of dyspnea seems to be influenced by psychogenic factors such as anxiety, patients with advanced cancer may experience severe dyspnea despite normal respiratory function test results. 6 Multidimensional assessment of dyspnea therefore is required to evaluate effectiveness of treatments. 7 In previous reports, nebulized furosemide was found to block chloride channels at several cellular sites in the airway, including mast cells, epithelial cells, and nerve. 8 Bianco et al. reported that furosemide inhalation prevented bronchoconstriction in patients with asthma by inhibiting of chloride secretion. 9 Nishino et al. reported that inhaled furosemide could prolong breath-holding time and alleviate experimentally induced dyspnea in normal volunteers. 10 Although an anecdotal report described inhaled furosemide treatment in cancer patients with uncontrolled dyspnea, 11 a clinical benefit of nebulized furosemide for dyspneic terminally ill cancer patients is not established. Based on the favorable preliminary evidence, we conducted an open clinical trial to investigate the effectiveness of nebulized furosemide in patients with advanced cancer whose dyspnea was uncontrollable by standard therapeutic measures. Our primary objective was to evaluate effect on subjective dyspnea, while the secondary objectives were to evaluate effects on objective respiratory data and also toxicity. Methods Eligibility for this study required a histologic diagnosis of malignant disease; presence of dyspnea resisting standard treatments, such as drainage of any pleural or pericardial effusion and administration of antibiotics for pneumonia, or diuretic therapy for cardiac failure; and the patient s informed consent. Patients with mental or cognitive disorders, or a change in medication for dyspnea within 24 hours before enrollment, were excluded. Twenty milligrams of furosemide diluted with 3 ml of normal saline was inhaled through an ultrasonic nebulizer over about 10 min. 12 Initial severity of dyspnea was assessed with the Hugh- Jones score. 13 Effects of nebulized furosemide were evaluated using the Cancer Dyspnea Scale (CDS) before treatment and 60 min following treatment. This scale, composed of 12- items, is a brief, self-rating reliable instrument for assessing dyspnea experienced by cancer patients. For this study, three variables, consisting of sense of effort, sense of anxiety, and sense of discomfort, were evaluated with this scale. 14 Hemoglobin oxygen saturation (SpO 2 ) and heart rate were measured with a pulse oximeter applied to a digit. Respiratory rate, heart rate, and arterial blood gas parameters also were determined before and 60 min after nebulization of furosemide. Results were analyzed using a paired t-test (paired Wilcoxon test). To evaluate adverse effects, patients were asked in a questionnaire whether they were troubled by cough, nausea, sleepiness, or other symptoms, using a 4-point scale ranging from Grade 0 (not at all) to 3 (very much). In addition, patients were asked whether they felt relief with the treatment, and whether or not they hoped to continue this treatment. The pathophysiological causes of dyspnea were evaluated by oncologists according to a previous classification. 15 Demographic and clinical characteristics were obtained from the patients medical charts. Results Fifteen patients who were admitted to the Department of Internal Medicine or the Palliative Care Unit at the National Sanyo Hospital between February and November 2001 were enrolled in this study. Characteristics of patients are summarized in Table 1. Seven patients received oxygen continuously by nasal cannula, and one used oxygen intermittently. The median amount of oxygen given was 2 liters per min. Twelve patients already had been administered systemic opioids for pain and dyspnea (morphine for 10 patients, median dose 30 mg/ day; codeine and buprenorphine, one each). Ten patients were receiving corticosteroid therapy (prednisolone-equivalent median dose, 15 mg/day). In most patients (87%), the intensity of dyspnea by Hugh Jones scoring exceeded Grade 4. The major causes of dyspnea were an increase in tumor size, pleuritis and/or pleural effusion, airway stenosis, anemia, and excessive sputum. Effects of nebulized furosemide upon subjective symptoms are shown in Figure 1. The total

3 964 Kohara et al. Vol. 26 No. 4 October 2003 Grade of Primary Dyspnea by Current Medication Table 1 Demographic and Clinical Characteristics of Subjects Causes of Dyspnea Tumor Clinical Hugh-Jones Increase Pleuritis Airway Case Age Sex a Site PS b Stage c Oxygen steroid opioid d Score of Tumor Effusion Atelectasis Stenosis Pneumonitis Pericarditis Sputum Anemia Cachexia M lung 2 IV M F breast 2 R M M stomach 3 IV B F lung 3 IV M lung 4 IV M F lung 3 R M M lung 3 IV F breast 4 R M M lung 4 IIIB F ovary 3 R M M lung 2 R M M bladder 3 IV M M lung 3 IV M F lung 3 IIIB C M stomach 3 IV M 4 a M = male, F = female. b PS = performance status. c R = recurrent. d M = morphine, B = buprenorphine, C = codeine.

4 Vol. 26 No. 4 October 2003 Nebulized Furosemide for Dyspnea 965 Fig. 1. Effects of nebulized furosemide on dyspnea using the Cancer Dyspnea Scale (CDS). The total dyspnea score at 60 min after inhalation of furosemide was significantly decreased compared with that before treatment. Furthermore, scores for both sense of effort and sense of anxiety also were significantly improved. CDS dyspnea score significantly decreased after nebulization (P = 0.007), and scores for both sense of effort and anxiety also were significantly decreased (P = and P = 0.04, respectively). However, objective data such as PaO 2, PaCO 2, SpO 2, heart rate, and respiratory rate showed no significant change (Table 2). Twelve patients (80%) considered this treatment as effective, and nine (60%) desired continuation of the treatment. Grade 2 nausea was experienced by one patient, and Grade 1 sleepiness and nausea by three patients. However, these adverse events improved within a few hours and no severe toxicities were observed during treatment. In this study, total CDS dyspnea scores improved in 12 of 15 patients. We therefore compared characteristics and objective data between these 12 patients and findings in the three for whom this treatment was ineffective. Administration of oxygen, corticosteroid, and opioid, performance status, Hugh Jones score, age, sex, PaO 2, PaCO 2, SpO 2, HR, RR, cause of Table 2 Physiologic Effects of Nebulized Furosemide After Before (60 min) P value PaO 2 (Torr) PaCO 2 (Torr) SpO 2 (%) Heart rate/min Respiratory rate/min SpO 2 = hemoglobin oxygen saturation; PaO 2 = partial pressure of oxygen in arterial blood; PaCO 2 = partial pressure of carbon dioxide in arterial blood. dyspnea, sense of dyspnea score, sense of anxiety score, sense of discomfort score, and total CDS dyspnea score showed no significant differences. Patients whose dyspnea was caused by a tumor increase or pneumonitis tended to obtain insufficient relief from this treatment (P = 0.36 and 0.37 respectively by Fisher s exact probability test). Discussion We showed that inhalation of nebulized furosemide alleviated the sensation of dyspnea according to decreased CDS scores for sense of effort, sense of anxiety, and total dyspnea. However, objective data such as PaO 2, PaCO 2, SpO 2, HR, and RR did not change with treatment. These findings confirmed the results of a previous report in which inhalation of nebulized furosemide resulted in a remarkable reduction of severe dyspnea in three terminal cancer patients. 16 The mechanism of alleviation of dyspnea by furosemide has not been fully elucidated. In patients with mild asthma, furosemide has a protective action against a wide range of bronchoconstrictive stimuli that act indirectly on airway smooth muscle, including exercise, allergens, and adenosine. 9,10,17 Nishino et al. reported that nebulized furosemide prolonged breath-holding time and alleviated respiratory discomfort in healthy subjects, and hypothesized that activation of pulmonary stretch receptors and inhibition of vagal irritant receptors

5 966 Kohara et al. Vol. 26 No. 4 October 2003 might play a role. 10 However, Robuschi et al. reported that only a small portion of nebulized furosemide (no more than 10%) reached the airways, while the remainder was exhaled or ingested. 18 Thus, though the mechanism of local action of nebulized furosemide remains unclear, its effectiveness for dyspnea in patients with advanced cancer remained an important clinical issue. In this study, scores for both sense of effort and sense of anxiety improved significantly after inhalation of nebulized furosemide (P = and P = 0.04, respectively). Sense of effort was interpreted as a reflection of the pathophysiologic aspects of dyspnea, which are related to physical activity. 8 On the other hand, sense of anxiety reflected the psychological nature of dyspnea. We know of no evidence that furosemide is effective against anxiety per se. One might explain that the decrease in this subscale reflected a secondary psychological effect consequential to an improved pathophysiologic state. No severe adverse effects occurred in this study. Cough, sputum production, and nausea were the most common toxicities, but these were tolerated and were easily managed. Several limitations to our study indicate a need for caution in interpreting the findings. First, because this was an uncontrolled open study, the results might include a placebo effect. Second, assessment of dyspnea was conducted on just only two occasions, before and after administration of a single dose; this might be inadequate as a means of evaluating dyspnea of patients with advanced cancer. However, in previous reports, relief of dyspnea was noted by 15 to 20 min after initiation of nebulized furosemide with a reported duration of effect of 6 to 12 hours. 9,16 Accordingly, we considered 1 hour after treatment to nebulization be a reasonable time point for evaluating the effect of furosemide. Third, the sample size was small, and backgrounds of participants were heterogeneous. To definitively determine the effects of nebulized furosemide, a double-blind controlled study is required. In conclusion, our preliminary data suggest that inhalation of nebulized furosemide may alleviate the sensation of dyspnea in patients with advanced cancer. We also confirmed feasibility of administering this treatment. Full establishment of effectiveness of inhalation of nebulized furosemide for uncontrollable dyspnea in patients with advanced cancer awaits a randomized controlled study. Acknowledgments The authors are grateful to Kenichi Gemba, MD, PhD, of the Department of Internal Medicine, Okayama Rosai Hospital, for assistance with their research. We also thank to Naohito Shimoyama, MD, PhD, Division of Pain and Palliative Care, National Cancer Center Hospital, for his useful comments. This work was supported in part by a Grant-in-Aid for Cancer Research (12-2) and Medical Frontier Strategy Research from the Ministry of Health, Labor, and Welfare of Japan. References 1. Cowcher K, Hanks GW. Long-term management of respiratory symptoms in advanced cancer. J Pain Symptom Manage 1990;5: Manning HL, Schwartzstein RM. Pathophysiology of dyspnea. N Engl J Med 1995;333: Bruera E, Ripamonti C. Dyspnea in patients with advanced cancer. In: Berger A, Portenoy RK, Weissman DE, (eds). Principles and practice of supportive oncology. Philadelphia: Lippincott-Raven, 1998;23: Higginson I, McCarthy M. Measuring symptoms in terminal cancer: are pain and dyspnea controlled? J R Soc Med 1989;82: Ruben DB, Mor M. Dyspnea in terminal cancer patients. Chest 1986;89: Maltoni M, Pirovano M, Scarpi E, et al. Prediction of survival of patients terminally ill with cancer. Cancer 1995;75: Bruera E, Schmitz B, Pither J, et al. The frequency and correlates of dyspnea in patients with advanced cancer. J Pain Symptom Manage 2000; 19: Bianco S, Vaghi A, Robushi M, et al. Prevention of exercise-induced bronchoconstriction by inhaled furosemide. Lancet 1988;2: Bianco S, Pieroni MG, Refini RM, et al. Protective effect of inhaled furosemide on allergen-induced early and late asthmatic reactions. N Engl J Med 1989;321: Nishino T, Ide T, Sudo T, et al. Inhaled furosemide greatly alleviates the sensation of experimentally induced dyspnea. Am J Respir Crit Care Med 2000;161:

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